Conclusion: Putting Theory Into Practice

Dr. Willis C. Maddrey, MD

WILLIS C. MADDREY, MD: Now, what we’ll do here is we will take a case or two, depending on the time and the number of questions that you have sent in, and we will discuss this case in light of what you’ve heard. Dr. Schiff will be working on the questions that come in. I imagine some of them have already been answered during the period of time. And I will have our panel comment on a few issues, also.

The first patient that we’ll discuss is a 30-year-old female marketing executive who was diagnosed with HCV in 1994. At the time the patient was completely asymptomatic, had an ALT of 88, AST of 62 and was anti-HCV positive. There was a history of a blood transfusion given in Mexico following an automobile accident at age 19. She had actually at that time received six units of blood. A liver biopsy was done based on this information, and it showed minimal portal fibrosis…I mean minimal portal inflammation and no fibrosis at all.

The HCV RNA, which used the BDNA assay, showed 84.5 equivalence per mL and she was found to be HCV genotype 1b. So lots of information was available. This patient was completely evaluated, and you had a very good profile on what you were dealing with here of a patient who had evidence of inflammation and was 1b and had had the disease for some time.

She received interferon monotherapy at standard doses from June 1994 to January 1995, with the typical dosing for that period of time. She tolerated the drug well, and her ALT returned to normal. She stopped the treatment. In May of 1995, 4 months later, the ALT had come back even higher than she had been before at 230, and now the HCV RNA, again by the same assay, was back at 32.6. Now, she declined to restart therapy for several reasons, the main one being that she wanted to become pregnant and was concerned…she’d not been pregnant before…and was concerned that if she kept taking time out for this she might not get pregnant at an appropriate interval.

However, in November 1995, she was seen in a follow-up visit 11 weeks pregnant, and her ALT was still above the limit of normal for that laboratory. She delivered a healthy baby in May 1996. In June 1996, in a follow-up visit one month later the HCV RNA now by a PCR test was rather high…3,183,000 copies. She again refused treatment because she wanted to get pregnant again. And she asked what the risks were, and of course after considering all the risks she made the decision to delay therapy. She was followed, and during the period of May 1996 to October 1998, she continued having elevated ALT’s and continued with a relatively level viral load. She had a second child during that interval. Now, when she relapsed again and had gotten to the point that she didn’t want to have any more babies at the moment, we talked about interferon/ribavirin combination therapy, which was begun in late 1998. The treatment was generally well-tolerated, with the exception of a drop in hemoglobin. Not an unusual drop. She was started at 1,000 milligrams of ribavirin based on her weight, and she dropped from 14.4 to 10.4 without incident, but the dose was reduced to 600 milligrams based on this, and her hemoglobin stabilized.

Follow-up at 6 months posttreatment revealed an ALT normal of 28 and an HCV RNA undetectable by PCR. Now, this is 6 months, so she is a sustained responder. So the discussion questions are listed here. And I think we’ve covered several of these, but I will ask our different panel members to comment. I’d like for each of you to consider this, too. You had a woman who’s had this disease for a long time, and she had wanted not to be treated for good and valid reasons…what many of you would consider good and valid reasons. Would you continue therapy for an additional 6 months? Would you have? Now, I’ve already told you that she had a sustained response, so John, would you go over just for a second a little bit of your thinking about this. Should this woman who had relapsed have really taken the treatment longer? I’ve already told you she was in the high-risk genotype. Or is that just a statistical type thing?

JOHN G. McHUTCHISON, MD: Well, I think she’s at high risk for relapse according to the data that Ira presented. I think I’d probably treat her for another 6 months.

WILLIS C. MADDREY, MD: Most people…anyone on the panel who would not have treated this relapser, 1b, for 1 year? The answer is no. Now, let’s talk about the other side of that coin. Suppose she were a type 3, an unusual type. Suppose she were a type 3, and she had had these relapses, and she did tell me that she wanted after she got well, she did want to get back into the baby manufacturing business. And so she wanted us to get it right this time. Would you have stopped at 6 months if she had had just a very good response? Bruce, let’s ask you. How confident are you on this 6-month, 12-month thing that we’ve heard about so much?

BRUCE R. BACON, MD: I would have treated her for 6 months if she was genotype 2 or 3, but if she would have relapsed after that, I would have re-…if she was willing, I would have re-treated her for a year then.

WILLIS C. MADDREY, MD: All right.

BRUCE R. BACON, MD: But I would have gone 6 months if it was that genotype.

WILLIS C. MADDREY, MD: I’d like to see a show of hands of the audience. How many of you believe that genotype 2 or 3 in this situation should be treated for just 6 months? Okay. How many of you believe that regardless of genotype…in fact, we shouldn’t even do genotype, we should just go in and treat everybody for a year? How many of you just don’t care? (Laughter) No, I don’t want to know that. You know, we’re just trying to get right down to this. There are a sufficient number in the audience who are still uncertain about this matter, and you must understand this is relatively new information. The purpose tonight is to focus on things we’ve learned in the past year, not a primer on hepatitis C. And one of the things that has changed in the last year in the hepatitis C world is just that: A real reason now for genotyping that up until before a year ago I don’t think there was general agreement for the role of genotyping. But if you believe what we just talked about, and there’s obviously some belief in here, then you will start doing genotyping, won’t you?

Now, if she wishes to have another child, how long after she stops taking ribavirin therapy…because that’s the risk…should she wait before it’s safe for her to become pregnant? This woman gets pregnant remarkably easily. From the time she has been interested in getting pregnant, it’s been a matter of really hours. (Laughter) So let’s go to Ira Jacobson. How long would you ask her to wait because the ribavirin is on board, a very very practical question.

IRA M. JACOBSON, MD: That’s a very important question because of the invariable teratogenicity of ribavirin in laboratory studies. And here we have to go by the recommendation of the manufacturer, which is that tissue washout studies, if you can call them that, have shown that it takes 6 months to be absolutely sure that every trace of this drug is gone. So the current recommendation is that you must wait for 6 months after the last dose. And that goes for either the male or the female, according to current recommendations.

WILLIS C. MADDREY, MD: Now, that’s a very important one. I’m going to ask Dr. Schiff to comment on that. What about this idea that we ought to take the same kind of contraceptive precautions in the male receiving ribavirin? Dr. Schiff?

EUGENE R. SCHIFF, MD: Yeah, Willis. I’m asked that frequently, and I don’t think there is any data that a male who went ahead and his wife became pregnant and was taking the drug and there was a congenital defect. But I think because of the potential for it that we should be prudent and use some sort of contraceptive barriers that some of these macho men don’t want to do.

WILLIS C. MADDREY, MD: Yes. Thank you for that, Dr. Schiff. (Laughter) I’m not even sure it’s just the macho men when you get right down to it. (Laughter) But I think it is prudent for us to recommend to the male, based on what we know . You know, even with the best of contraceptive advice, people will get pregnant, and then you’re in a bit of a dilemma as to what to recommend. There is not sufficient evidence right now to answer that question, as most in the audience know. But I will say that from what we do know with 20 or 30 cases, fetal wastage is rather remarkably high, suggesting that this teratogenic effect is real in this situation.

What would you do with this patient? Let’s say she’s three months into that course. Remember she had had to have her dose of ribavirin reduced. And many people, including myself, if I have to reduce ribavirin, I reduce down to 600 or so. Would you think, based on current evidence, that after a month or so when she’s restabilized you ought to try to creep her back up to 800? Let’s go to Bruce about that.

BRUCE R. BACON, MD: Well, there isn’t much current evidence that we are aware of. There has been a dose-finding study. Those results are…have not been publicized yet. I probably would have tried to increase her dose up to 800 and monitor her hemoglobin hematocrit and see…and her symptoms and see. If she can tolerate that, I’d try and get her up to 800. Her hemoglobin went up to about 11 1/2, so she probably would have been able to tolerate up to 800.

WILLIS C. MADDREY, MD: Now, John Wong has told us about economic modeling. Would you give her a drug that might help her have a higher hemoglobin, such as Epogen?

JOHN B. WONG, MD: Well, it’s not been clear to me. It seems to me that when you are that anemic from hemolysis, your endogenous erythropoietin level is probably pretty high. But I don’t know…I’ve never used Epogen in that setting, and I don’t know the answer. I’d have to know…

WILLIS C. MADDREY, MD: Dr. McHutchison I think has a little bit of experience with this.

JOHN G. McHUTCHISON, MD: I’d just like to say that in the initial treatment studies that we’ve talked about tonight, the patients who dose-reduced ribavirin to 600 milligrams did not have a decreased or a diminished sustained virologic response rate.

WILLIS C. MADDREY, MD: All right. That’s an important trend that I think we all must watch. Now, Dr. Schiff has a question or two that apply to this.

EUGENE R. SCHIFF, MD: Germane to relapse in this case. Here’s a good one, Willis. Comes up all the time. And I’m going to ask John this, John McHutchison. What’s the relapse rate on follow-up of initial responders to combination therapy? And if they do relapse, John, how do you handle them? Do you re-treat them? Do you re-treat them for a longer period of time? What are you recommending, although we don’t have the data we need?

JOHN G. McHUTCHISON, MD: This is relapse after initial treatment?

EUGENE R. SCHIFF, MD: After combination therapy. In other words, combination therapy. They relapse. What do you recommend?

JOHN G. McHUTCHISON, MD: Well, I think if they’ve been…the most common situation that that has occurred to me so far is somebody who’s been treated for 6 months in the community without HCV genotyping. In that situation, if on genotyping subsequently after the relapse, they’re genotype 1, I believe they should be re-treated for a year.

EUGENE R. SCHIFF, MD: One other question that I think is a very practical one. If you have a patient who’s on monotherapy right now…often they were started before combination was even available. But you’ve got them on therapy right now, and they have gone into remission. Bruce, would you add ribavirin to this patient’s interferon in the hope that you are going to reduce the relapse rate?

BRUCE R. BACON, MD: If they’re HCV RNA is negative (Overlap)

EUGENE R. SCHIFF, MD: PCR.

BRUCE R. BACON, MD: If their RNA is negative on monotherapy, I would just have kept them on monotherapy and keep my fingers crossed that that’s sufficient. If they’re RNA positive between 3 and 6 months, when you’re trying to decide if you’re going to take them off, I have added ribavirin in that situation when it first became available. And those patients…number one, they tolerate the additional ribavirin exceptionally well, and they have become negative.

EUGENE R. SCHIFF, MD: And…but what…

BRUCE R. BACON, MD: Usually that’s in a situation where the virus has gone done.

EUGENE R. SCHIFF, MD: So you would say…

BRUCE R. BACON, MD: I’d add it.

EUGENE R. SCHIFF, MD:…okay, if they’re already in viral remission you’d stop, and if they relapse then retreat.

BRUCE R. BACON, MD: Yes. I must say, I’ve been adding ribavirin. Ira, what are your thoughts?

IRA M. JACOBSON, MD: Given the compelling evidence that ribavirin added to interferon helps prevent relapse, as well as it’s associated with higher end of treatment response rates, I find it irresistible to just add the ribavirin. And the only dilemma I have is how long to add it for. But I generally do it for at least 6 months of combination therapy.

EUGENE R. SCHIFF, MD: Okay. Willis, I think we ought to go to the next case.

WILLIS C. MADDREY, MD: Well, we certainly got agreement then. Some did, some didn’t, and others did it half way. So I mean, I appreciate that clarification. (Laughter) Let’s go to the next case. This is a treatment-naive patient. This 42-year-old male executive who had had ALT elevated on several past occasions. He was diagnosed as having HCV a year ago with a slight elevation of ALT, and a qualitative HCV RNA and of course a positive anti-HCV. On careful questioning…that usually means the third visit…he did admit to IV drug use and shared needles 20 years ago, but he did not inhale. (Laughter) And this man had an additional thing of drinking six to eight glasses of wine on weekends, and actually on further questioning it was daily on weekends, and the weekend started on Thursday night. This is the kind of patient you all see. I imagine most in the audience can relate to a person in whom the story unfolds over a period of several months of questioning as you develop mutual confidence.

This patient, his overall health had been excellent, and his physical examination was unremarkable. The liver was questionably enlarged, and the spleen was palpable. It was definitely palpable. ALT was 245. AST was 80. Albumin was normal. Bilirubin was normal. And a liver biopsy, a bit to the surprise of the operator, showed much more liver disease than would have been suspected with chronic hepatitis, bridging fibrosis and early cirrhosis.

You’ll see some of what happened here. He was treated with interferon/ribavirin. Going across the ALT line, at baseline he was only 110. At 2 months, he was 36, 4 months 24, 6 months 32…that got within the normal range. And his HCV RNA by PCR test fell from 2,630,000 to 230,000 at 6 months, a marked drop but not to negative.

The discussions for the panel here on this case. Would you stop or continue therapy at this time? This man has had a 90 percent drop, and he has had a biochemical response. Let’s start with Dr. Bacon. This man got close but did not achieve at 6 months a response.

BRUCE R. BACON, MD: Well, Dr. McHutchison showed the data. I think he has a one percent chance of a sustained response. No?

JOHN G. McHUTCHISON, MD: Two.

BRUCE R. BACON, MD: Maybe two. Okay. I would stop.

WILLIS C. MADDREY, MD: All right. You would stop. How many in the audience would say, “Well, I’m not so sure. I got 90 percent of the way. I think I’ll give him 6 more months.” Yeah, that’s what I thought. I really think that’s more than half of the audience would have continued, thinking you’re so close. This is what we used to call a partial responder, and we’ve dropped that terminology out. Let’s ask John Wong.

JOHN B. WONG, MD: They’re nonresponders now.

WILLIS C. MADDREY, MD: Nonresponders. Partial responders are nonresponders. Please understand that. (Laughter) But this is an almost responder. (Laughter) And a lot of you out there are thinking that this is one of those almost responders, and John Wong, you’ve got to help us here because you’re holding al the money. (Laughter) If you were in charge of the insurance company and all the data that you’ve had here, and you were presented that, would you approve 6 more months of therapy that you would pay for? Let’s say that you’re in charge of one of the major companies.

JOHN B. WONG, MD: I believe, as a patient with…who has cirrhosis, if you put it in that context, who drinks alcohol substantially…and that’s probably why the liver biopsy showed such advanced disease. Dr. Schiff presented and will be published in the American Journal of Medicine a review of some of the alcohol effects in hepatitis C. Suffice it to say that roughly the rate of progression is doubled with that kind of alcohol intake, and if you then couple that with the likelihood that this fellow may progress on to either decompensated cirrhosis, for which there are limited treatments, and in fact, only one effective treatment…transplantation, which is rather expensive…you’re talking about perhaps spending $5,000 to buy a one or two percent chance and offsetting that against a fairly high chance that he’s going to progress on to decompensated cirrhosis of the liver.

WILLIS C. MADDREY, MD: John, would you approve the treatment? (Laughter)

JOHN B. WONG, MD: I think I would.

WILLIS C. MADDREY, MD: Good. That’s good. (Laughter) Okay. Just…Now…Dr. McHutchison, suppose…you’re interested in induction therapy. Suppose you said, “Look, this guy almost got there on standard therapy. Let’s just give him 5 million units of interferon a day and let’s really just raise the dose because we almost got it.”

JOHN G. McHUTCHISON, MD: I wouldn’t raise the dose, but I’d just continue on for another 6 months. I think we need to bring up Thierry Poynard…who is the author of one of the papers, and he looked at the five factors and a combination of them. And this fellow has four of those bad factors: He’s male, he’s older, he has cirrhosis and he has a high viral load before treatment. So he’s somebody that if you analyzed the data, depending on the number of bad factors you have, he should receive 48 weeks of therapy and he will statistically do better.

WILLIS C. MADDREY, MD: So you…with the knowledge…why don’t you handle that last one? Would knowledge of the genotype have changed you one way or the other? It sounds like it would have, if he had…

JOHN G. McHUTCHISON, MD: Well, he’s already got the four bad factors without knowing the genotype, so it may not have made a difference in this case.

WILLIS C. MADDREY, MD: Okay. Good. All right. Dr. Jacobson wants to comment.

IRA M. JACOBSON, MD: I don’t think the issue here is whether to continue for another 6 months in the hope of inducing a complete or a sustained remission. I think this case gets into the issue of maintenance therapy, and the underpinning of that is the evidence that interferon has independent anti-inflammatory and antifibrotic properties. To invoke Dr. Poynard again, I think he would say that his data show…would support the idea of keeping this patient on therapy indefinitely to retard the progression of fibrosis. I’m going out on a limb a little bit because that’s certainly not an approved indication for interferon…

EUGENE R. SCHIFF, MD: I don’t think you are. Because, you know, the NIH is doing a trial where they’re going to be looking at people who didn’t clear virus, who have early cirrhosis or have significant septal fibrosis and see if long term interferon treatment changes the natural history of that cirrhosis and if it reduces the risk of hepatocellular carcinoma. So I don’t think you are . and we discuss that at one of the symposia today.

Willis, I’ve got some…a few questions that are germane to this kind of patient. And its more from the epidemiologic standpoint. We’ve touched on it. I think we’re all faced with this. Let’s say your man here who’s given a big donation to your university, Willis, asked you, “Can I have one or two drinks at dinner with my wife? I’ve been doing that for years. I’m not in trouble anymore, Dr. Maddrey.”

WILLIS C. MADDREY, MD: Well, it would depend on whether he’d given us the money or left it in his will. (Laughter)

EUGENE R. SCHIFF, MD: Okay. I think the point is…

WILLIS C. MADDREY, MD: Remember, my day job is as an administrator.

EUGENE R. SCHIFF, MD: I think the point is unequivocally they have to abstain from alcohol when you treat them. And there’s an overwhelming amount of data to support that. Now, just real quickly, because he had a history of some IV drug use, John Wong, from you standpoint, and this is I think a good question because it’s such a common type patient. Let’s say he wasn’t such a big drinker. Is the natural history of people who acquired this as a teenager sharing a needle different than the other patients. In other words, what they’re getting at is it milder or really doesn’t have anything to do with it?

JOHN B. WONG, MD: I think there have been several studies comparing the natural history of the disease, both in patients who have acquired through transfusion and through IV drug abuse. And it’s a mixed bag, but the net sum of it I think is it’s roughly about the same.

EUGENE R. SCHIFF, MD: One last question about the background of this patient. Let’s say he used IV drugs a little more than we thought, and, Bruce, he picked up HIV. We all get asked this, and I’m going to be more specific about it. If he was C-positive and HIV-positive and had a cd4 count of about 400, what about combination therapy in the face of the combination therapy he’s taking for HIV? There have been some concerns raised. But is there any danger there to support an interaction that might be adverse?

BRUCE R. BACON, MD: I don’t know the answer to that question. Ask somebody else.

EUGENE R. SCHIFF, MD: Who wants to answer that? Ira, get in on that.

IRA M. JACOBSON, MD: My ID colleagues tell me that they’re worried about ribavirin undermining the efficacy of…

EUGENE R. SCHIFF, MD: Right.

IRA M. JACOBSON, MD:…d4T and AZT. So the first thing I’d do is talk to my ID colleague and ask if there’s a regimen he can put them…put the patient on that doesn’t include those drugs. If he can do that, then I’d go ahead and give interferon and ribavirin.

EUGENE R. SCHIFF, MD: I don’t think there’s been any data even with those drugs, but theoretical. In other words, we’re concerned, but I don’t think (Overlap)

IRA M. JACOBSON, MD: In terms of in vitro studies.

EUGENE R. SCHIFF, MD: Willis, maybe we ought to go to that last case.

BRUCE R. BACON, MD: The next time I get asked that, I’ll call Ira.

WILLIS C. MADDREY, MD: Well, actually we’re not going to do the last case because even though we couldn’t start on time, I think it’s important we finish on time because many of you have had a long day by the pool. (Laughter) So…but I want to make a few comments about what we…what I think we’ve learned in the last year. And I believe you’ve seen a great deal of it exhibited here tonight in the five short talks and in the cases. And try to think just a moment with me of what you know about hepatitis C and when you learned it. All of us realize that hepatitis C is just about at its tenth birthday as being discovered, and all of you know and saw the staircase effect of monotherapy interferon going first for 6 months and then going to 12 months, and you realize those rather poor results.

Many have questioned who were not active in the field were we fooled? Why did we have reports of such good early results and now we’re reconsidering? And I think the reason is very clear. And particularly in the last year, the bar has been raised so high. In the early monotherapy studies, we were looking at biochemical responses at 6 months, and we were getting 40 percent. And then we started using virologic studies. But the virologic studies were relatively crude; the earlier measures weren’t very good. And now we have better virologic studies.

And then we started adding the concept of sustained response. And I don’t believe any paper can get into a legitimate journal now that does not report its results based on virologic response 6 months after the end of therapy. So when we’re talking today about a 30 to 40 or 45 percent response with combination therapy, we’re really talking about holding it to a new and higher standard.

Now, what’s happened new this year is this appreciation of a reason for genotyping. What else has happened new this year is an appreciation that there’s more of this than we realized, and case finding is so crucial to what we’re doing. I think all of you are seeing that it’s better to treat early before cirrhosis for two or three major reasons, not the least of which is that in hepatitis C, the cancer clock starts ticking when cirrhosis develops. This is not as true with hepatitis B, as you know. We can have a cirrhotogenic hepatocellular carcinoma without cirrhosis, but in the experience of…I think I questioned everyone on the panel…we just rarely if ever see anyone develop a hepatocellular carcinoma without having developed cirrhosis. So I think that’s a telling reason for going earlier with a treatment.

Now, the question is…and this is the question of today. Where on the spectrum should we draw the lines, the earliest line and the latest line? We all agree…and I think most of you would, too…that the later line is you stop using these treatments if a patient has cirrhosis that is decompensated with one of the major complications…bleeding, ascites, spontaneous sepsis. The big issue is how early is early? You heard some differing opinions alluded to throughout this conference about whether or not to treat normal ALT cases. I think the jury is still out on this, and I hope while the jury is still out most of you will be referring patients to trials so that we can answer it.

Another thing that’s relatively new, or at least came completely to the fore this year, is the important role of alcohol in causing progression to the complications. The combination of alcohol and hepatitis C-induced cirrhosis is the single strongest predisposer to hepatocellular carcinoma in the United States, far more than it is of hepatitis B in any of its forms, in large measure because of the number of cases we have.

I think we’ve learned that you really have to treat your relapsers. You have to go back and case find people that you were disappointed with because of relapsing a few years ago. I think we’ve learned a lot about ribavirin this year. We know…and I think the dose is not going to have to be quite as high, but we’ll wait for studies. I must say that I think 600, 800, l,000 is sort of the range and not the higher range. You must check that hemoglobin. I had a patient referred to me recently who had started out with a hemoglobin of 16 and was referred to me six weeks later with a hemoglobin of five and had not been checked in between. Well, that was just unnecessary. The patient came around nicely, came around very nicely without anything except time being done, but that’s unnecessary. I think we have to put more attention on the contraception because that is just a tragedy waiting to happen if you overlook it.

So what we’ve got now is a reason to treat a large number of people with C that you might have become discouraged with a couple of years ago. You also realizer that the whole area of nonresponders is under active review. It’s in that area that combination therapy with or without induction therapy just awaits trial.

So what don’t we know? What can we expect? In his earlier remarks, Eugene mentioned several of the possibilities: various protease inhibitors, polymerase inhibitors, helocase inhibitors. There’s a race on out there. Hopefully someone will find a new drug. The PEGylateds are right around the corner. That’s the next thing we’re going to discover, the ribozymes are out there. They may or may not work. Antiscinsologonucleotides (?) may work. A lot of things may work, and we do have time.

What I would suggest to you is that the story is a lot clearer than it was a year ago, and that it continues to unfold at a rapid rate. I believe that part of the excitement of hepatology these days is the ability to start thinking about 40 percent sustained responses because many of you know, whereas the AIDS physicians tell us…the HIV treaters…that they never announce a cure, that they feel that they are not sure they can ever cure anyone of HIV infection. It seems that maybe we can cure hepatitis C or at least put it in remarkable sustained remission. Remember the studies from several parts of the world, that if you get a sustained response and it’s held for the 6 months, you have a 90 percent chance that that response will still be holding 3 years later. And the only reason I don’t say 5 is the numbers are too small for that.

So we appreciate your coming tonight, and we hope you all learned something about at least what we know and what we don’t know. You realize we didn’t touch on lots of stuff tonight. We didn’t touch on co-infection with hepatitis B. We didn’t touch on co-infection with HIV. We didn’t touch on how to prevent cancer. All of these things are for another day. But for tonight, we surely appreciate your participation and hope you’ll go forth and have a fine meeting here at DDW. Thank you.

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